This invention relates to substituted azoles and to their use for treating TNFxcex1 and IL-1 mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis.
Accordingly the present invention provides a compound of formula I 
wherein
a is N or C;
b is CH when a is N, or O when a is C;
xe2x95x90 denotes a single or a double bond dependent upon whether the azole ring is an imidazole or an oxazole ring;
Z is N or CH;
W is xe2x80x94NR6xe2x80x94Yxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94,
where R6 is H, C1-C4alkyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-3alkyl, C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl, and xe2x80x94Yxe2x80x94 is C1-C4alkylene or a direct bond;
R2 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from halo, CF3, cyano, amido or thioamido, carboxylate or thiocarboxylate, C1-C4alkoxy, C1-C4alkyl, or NH2 which is optionally mono- or di-N-C1-C4alkyl substituted;
R3 is H, halogen, C1-C10alkyl, C1-C4alkenyl, C3-C10cycloalkyl, C3-C18heterocycloalkyl, C6-C18aryl, C3-C18heteroaryl, or methyleneaminoguanidinyl (i.e. xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94C(NH).NH2), each of which is optionally substituted by up to 4 substituents separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, halo-substituted-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl, optionally mono- or di-N-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom;
R5 is C6-C18aryl, C3-C18heteroaryl, or C3-C12cycloalkyl each of which is optionally substituted by up to 4 substituents separately selected from C1-C4alkyl halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkythio, or optionally mono- or di-N-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom,
and esters thereof and acid addition salts thereof.
Above and elsewhere in the present description the terms halo or halogen denote I, Br, Cl or F.
In a particular embodiment the invention provides a 4-phenyl-5-[(2-substituted)-4-pyrimidyl or -pyridyl]-oxazole of formula I, or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof (wherein the numbering of the atoms of the oxazole ring is shown below in formula II.)
Thus in a particular embodiment the invention provides a compound of formula II 
wherein
Z is N or CH;
W is xe2x80x94NR6xe2x80x94Yxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94,
where R6 is H, C1-C4alkyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C3alkyl, C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl, and xe2x80x94Yxe2x80x94 is C1-C4alkylene or a direct bond;
R12 is phenyl optionally substituted by one or more substituents, each of which is independently selected from halo, CF3, cyano, amido or thioamido, carboxylate or thiocarboxylate, C1-C4alkoxy, C1-C4alkyl, or NH2 which is optionally mono- or di-N-C1-C4alkyl substituted;
R13 is H, halogen, C1-C10alkyl, C1-C4alkenyl, C3-C10cycloalkyl, C3-C18heterocycloalkyl, C6-C18aryl, C3-C18heteroaryl, or methyleneaminoguanidinyl (i.e. xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94C(NH).NH2), each of which is optionally substituted by up to 4 substituents separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-4alkoxy, C1-4alkylthio, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl, optionally mono- or di-N-C1-4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom;
R15 is C6-C18aryl, C3-C18heteroaryl, or C3-C12cycloalkyl each of which is optionally substituted by up to 4 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, or optionally mono- or di-N-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
When R13 is heteroaryl it is preferably pyridyl (e.g. 4-pyridyl) or pyrimidyl, each optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, hydroxy, C1-C4alkoxy, carboxy, optionally C1-C6-alkyl or C1-C6alkoxy substituted carbonyl, or optionally mono- or di-N-C1-C4alkyl substituted amino.
When R13 is cycloalkyl it is preferably C3-C8, especially C5-C6cycloalkyl (e.g. cyclohexyl), optionally substituted, e.g. by 1 or 2 substituents, separately selected from C1-C4alkyl, halogen hydroxy, C1-C4alkoxy, or optionally mono- or di-N-C1-C4alkyl substituted amino.
When R13 is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, e.g. N or O, and is optionally substituted, e.g. by 1 or 2 substituents, separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, hydroxy, C1-C4alkoxy, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl, or optionally mono- or di-N-C1-4substituted amino.
When R15 is aryl it is preferably phenyl. When R15 is cycloalkyl, it is preferably C3-C7cycloalkyl, e.g. cylopropyl, cyclopentyl, cyclohexyl or cycloheptyl. R15 may be unsubstituted or substituted, conveniently mono-substituted, e.g. phenyl conveniently meta or para substituted, by halogen, C1-C10alkyl, halo-substitued C1-C10alkyl, C1-C10alkoxy, hydroxy, or xe2x80x94NR7R8, where R7 and R8 are idependently H, C1-C6alkyl, C6-C10aryl, C6-C10heteroaryl, C7-C11aralkyl or C7-C11heteroaralkyl.
When Y is C1-C4 alkylene, it is preferably C1-C2 alkylene, and is optionally substituted, e.g. by C1-C4alkyl (e.g. methyl), halogen, hydroxy, C1-C4alkoxy, or amino.
More preferably R12 is phenyl substituted, preferably mono- or di-substituted, by halogen or a halogen-containing group, e.g. 4-fluorophen-1-yl, or 3-CF3, 3-Cl, or 3,4-difluoro substituted.
More preferably R13 is H, C1-6alkyl, C1-C4alkenyl, phenyl, pyridyl, morpholinyl, piperidinyl, piperazinyl, or N-mono- or di-C1-4alkylamino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, hydroxy, C1-C4alkoxy, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl, or optionally mono- or di-N-C1-C4alkyl substituted amino.
Preferably W is xe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, where Yxe2x80x2 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94 or a direct bond
Thus in preferred embodiments the invention provides a compound of formula IIxe2x80x2
wherein
R15xe2x80x2 is phenyl or C3-C7cycloalky each of which is optionally mono-substituted by halogen, C1-C10alkyl, C1-C10alkoxy, hydroxy, trihalomethyl or xe2x80x94NR7R8, where R7 and R8 are independently H, C1-C6alkyl, C6-C10aryl, C6-C10heteroaryl C7-C11aralkyl or C7-C11heteroaralkyl;
R10 is halogen, CF3, cyano, amido, thioamido, amino C1-6alkyl;
R13xe2x80x2 is H, C1-C6alkyl, C1-C4alkenyl, phenyl, pyridyl, morpholinlyl, piperidinyl, piperazinyl, or N-mono- or di-C1-C4alkylamino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, hydroxy, C1-C4alkoxy, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl or optionally mono- or di-N-C1-C4alkyl substituted amino;
Z is N or CH and
Wxe2x80x2 is xe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, where Yxe2x80x2 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94 or a direct bond,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
Preferably R15xe2x80x2 is unsubstituted or monosubstituted by halogen, C1-4alkyl (e.g. methyl), C1-4alkoxy (e.g. methoxy), hydroxy or CF3.
Preferably R10 is halogen, e.g. F, or CF3.
Preferably R13xe2x80x2 is C1-C6alkyl, morpholinyl, piperidinyl, piperazinyl, or N-mono- or di-C1-C4alkylamino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl optionally substituted by hydroxy, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl or amino.
Preferably Wxe2x80x2 is xe2x80x94NHxe2x80x94Yxe2x80x3xe2x80x94 where xe2x80x94Yxe2x80x3xe2x80x94 is xe2x80x94CH2, xe2x80x94CH(CH3)xe2x80x94 or a direct bond.
The Invention includes the following compounds of formula II:
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-N-morpholinyloxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-N-piperidinyloxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-(4-ethoxycarbonylpiperazin-1-yl)oxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-(4-methyl-piperidine-1-yl)oxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-(4-ethyl-piperazin-1-yl)oxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-N,N-diethyl-aminooxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-(4-NH-piperidine-1-yl)oxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-(4-N-acetyl-piperidine-1-yl)oxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-(4-pyridyl)oxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-(1-piperazinyl)oxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-(1-amino-1-methyl)ethyloxazole;
4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-2-(1-hydroxy-4-methylpiperidine-1-yl)oxazole;
4-(4-Fluorophenyl)-2-(1-hydroxy-4-methyl)piperidine-1-yl)-5-(2-[cyclopropylmethyl]amino-4-pyridyl)oxazole;
4-(4-Fluorophenyl)-2-(4-NH-piperidine-1-yl)-5-(2-(S)-phenylethyl)amino-4-pyridyl)oxazole;
4-(4-Fluorophenyl)-2-(4-NH-piperidine-1-yl)-5-(2-cyclopropylmethylamino-4-pyridyl)oxazole;
4-(4-Fluorophenyl)-2-(4-N-(2-hydroxy-2-methyl)propylpiperidine-1-yl)-5-(2-cyclopropylmethylamino-4-pyridyl)oxazole;
4-(4-Fluorophenyl)-5-(2-cyclopropylmethylamino-4-pyrimidyl)-2-(4-NH-piperidine-1-yl)oxazole;
4-(4-Fluorophenyl)-2-(1-hydroxy-4-ethyl)piperidin-1-yl)-5-(2-cyclohexylamino-4-pyridyl)oxazole;
4-(4-Fluorophenyl)-2-(1-hydroxy-4-ethyl-piperidin-1-yl)-5-(2-cyclopropylamino-4-pyridyl)oxazole;
4-(4-Fluorophenyl)-2-(4-N-(2-hydroxy-2-methyl)propylpiperidine-1-yl)-5-(2-cyclohexylamino-4-pyridyl)oxazole;
4-(4-Fluorophenyl)-2-(4-N-(2-hydroxy-2-methyl)propylpiperidine-1-yl)-5-(2-cyclopropylamino-4-pyridyl)oxazole;
4-(4-Fluorophenyl)-2-(4-N-(2-hydroxy-2-methyl)propylpiperidine-1-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridyl)oxazole;
4-(4-Fluorophenyl)-2-(4-NH-piperidine-1-yl)-5-(2-cyclohexylamino-4-pyridyl)oxazole, and
4-(4-Fluorophenyl)-2-(4-N-(2-hydroxy-2-methyl)propylpiperidine-1-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridyl)oxazole.
In a further particular embodiment the invention provides a 1-[(2-substituted)-4-pyrimidyl]-2-phenyl-imidazole of formula I or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof. (The numbering of the atoms of the imidazole ring is shown below in formula III.)
Thus in yet further particular embodiments the invention provides a compound of formula III 
wherein
W is xe2x80x94NR6xe2x80x94Yxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94,
where R6 is H, C1-C4alkyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C3alkyl, C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl, and xe2x80x94Yxe2x80x94 is C1-C4alkylene or a direct bond;
R22 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from halo, CF3, cyano, amido or thioamido, carboxylate or thiocarboxylate, C1-C4alkoxy, C1-C4alkyl, or NH2 is which is optionally mono- or di-N-C1-C4alkyl substituted;
R23 is H, halogen, C1-C10alkyl, C1-C4alkenyl, C3-C10cycloalkyl, C3-C18heterocycloalkyl, C6-C18aryl, C3-C18heteroaryl or methyleneaminoguanidinyl (i.e. xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94C(NH)NH2), each of which may be optionally substituted by up to 4 substituents separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, halo-substitued-C1-4alkyl, hydroxy, C1-4alkoxy, C1-4alkylthio, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substitued carbonyl, optionally mono- or di-N-C1-4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom;
R25 is C6-C18aryl C3-C18heteroaryl, or C3-C12cycloalkyl each of which is optionally substituted by up to 4 substituents separately selected from C1-C4alkyl, halogen, halo-substituted-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, or optionally mono- or di-N-C1-C4alkyl substituted amino, or by N-hetereocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
When R23 is aryl, it is preferably phenyl optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, hydroxy, C1-C4alkoxy, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl optionally mono- or di-N-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom.
When R23 is heteroaryl it is preferably pyridyl (e.g. 4-pyridyl or 3-pyridyl), pyrimidyl, thienyl, furyl, or benzofuryl, each optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, hydroxy, C1-C4alkoxy, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl optionally mono- or di-N-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom.
When R23 is cycloalkyl it is preferably C3-C8, especially C5-C6cycloalkyl (e.g. cyclohexyl), optionally substituted, e.g. by 1 or 2 substituents, separately selected from C1-4alkyl, halogen, hydroxy, C1-4alkoxy, or optionally mono- or di-N-C1-4alkyl substituted amino.
When R23 is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, e.g. N or O, and is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, hydroxy, C1-C4alkoxy, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl optionally mono- or di-N-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom.
When R25 is aryl it is preferably phenyl. When R25 is cycloalkyl it is preferably C3-C7cycloalkyl, e.g. cylopropyl cyclopentyl, cyclohexyl or cycloheptyl. R25 may be unsubstituted or substituted, conveniently mono-substituted, e.g. phenyl conveniently meta or para substituted, by halogen, C1-C10alkyl halo-substituted C1-C10alkyl, C1-C10alkoxy, hydroxy or xe2x80x94NR7R8, where R7 and R8 are independently H, C1-C6alkyl, C6-C10aryl, C6-C10hetereoaryl, C7-C11aralkyl or C7-C11hetereoaralkyl.
When Y is C1-C4 alkylene, it is preferably C1-C2 alkylene, and is optionally substituted, e.g. by C1-C4alkyl (e.g. methyl), halogen, hydroxy, alkoxy, or amino.
More preferably R22 is phenyl substituted preferably mono- or disubstituted, by halogen or a halogen-containing group, e.g. 4-fluorophen-1-yl, or 3-CF3, 3Cl, or 3,4-difluoro substituted phenyl.
More preferably R23 is H, halogen, C1-6alkyl, vinyl phenyl, pyridyl, pyrimidyl, benzofuryl, furyl, thienyl morpholinyl, piperidinyl, nortropanyl, piperazinyl, methyleneaminoguanidinyl or N-mono- or di-C1-C4alkylamino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl optionally substituted by, halogen, hydroxy, C1-C4alkoxy, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl optionally mono- or di-N-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom.
Preferably X is xe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, where Yxe2x80x2 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94 or a direct bond. In particular X is xe2x80x94NHxe2x80x94CH(CH3)xe2x80x94.
Thus in preferred embodiments the invention provides a compound of formula IIIxe2x80x2
wherein
Rxe2x80x225 is phenyl or C3-C7cycloalkyl each of which is optionally mono-substituted by halogen, C1-C10alkyl, C1-C10alkoxy, hydroxy, trihalomethyl or xe2x80x94NR7R8, where R7 and R8 are independently H, C1-C6alkyl, C6-C10aryl, C6-C10heteroaryl C7-C11aralkyl or C7-C11heteroaralkyl;
R10 is halogen, CF3, cyano, amido, thioamido, amino or C1-C6alkyl;
Rxe2x80x223 is H, halogen, C1-C6alkyl, vinyl, phenyl, pyridyl, pyrimidyl, benzofuryl, furyl, thienyl, morpholinyl, piperidinyl, nortropanyl, piperazinyl, methyleneaminoguanidinyl or N-mono- or di-C1-C4alkylamino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, hydroxy, C1-C4alkoxy, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl, optionally mono- or di-N-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, and
Wxe2x80x2 is xe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, where Yxe2x80x2 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94 or a direct bond,
and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
Preferably Rxe2x80x225 is unsubstituted or monosubstituted by halogen, C1-4alkyl, (e.g. methyl), C1-4alkoxy (e.g. methoxy), hydroxy or CF3.
Preferably Rxe2x80x223 is halogen, vinyl, phenyl, pyridyl, pyrimidyl, benzofuryl, furyl, thienyl, piperidinyl, nortropanyl, or methyleneaminoguanidinyl, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl optionally substituted by hydroxy, halogen, hydroxy, C1-C4alkoxy, carboxy, optionally C1-C6alkyl or C1-C6alkoxy substituted carbonyl optionally mono- or di-N-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom
Preferably R10 is halogen, e.g. F, or CF3.
Preferably xe2x80x2 is xe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x3 where Yxe2x80x2xe2x80x3 is xe2x80x94CH(CH3)xe2x80x94 or a direct bond.
The Invention includes the following compounds of formula III:
3-Bromo-2-(4-fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)imidazole;
4-Bromo-2-(4-fluoromethylphenyl)-1-(2-cyclohexylamino-4-pyrimidyl)imidazole;
4-Bromo-2-(3-trifluoromethylphenyl)-1-(2-cyclopentylamino-4-pyrimidyl)imidazole;
4-Bromo-2-(3-trifluoromethylphenyl)-1-(2-cyclopropylamino-4-pyrimidyl)imidazole;
2-(4-Fluorophenyl)-4-(1-methyl-4-hydroxypiperidin-4-yl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl)imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl) 4-vinylimidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl) 4-(4-pyridyl)-imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl) 4-(2-pyridyl)-imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl) 4-(3-pyridyl)-imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl) 4-(2-thienyl)-imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl) 4-(2-furyl)-imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl) 4-(2-amino)pyrimidylimidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl) 4-(2-hydroxy)pyrimidylimidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl) 4-(2-morpholinyl)pyrimidylimidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl)-4-(3-thienyl)-imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl)-4-(2-benzofuryl)-imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl)-4-(5-chlorothiophen-2-yl)imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl)-4-(4-methoxyphenyl)imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl)-4-(4-fluorophenyl)imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl)-4-(3-chloro-4-fluorophenyl)imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl)-4-(3-chloro phenyl)imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenyl-ethyl]amino-4-pyrimidyl)-4-(4-methyleneaminoguanidinyl-imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-4-(4-ethoxycarbonyl)piperidine-1-yl imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-4-piperidine-1-yl imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-4-(4-formyl)-piperidine-1-yl imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-4-(4-(2-hydroxy-2-methyl)propylpiperidine-1-yl imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-4-(4-methyl)-piperidine-1-yl imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-4-(1-hydroxy-4-tert.butyloxycarbonyl)piperidine-1-yl imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-4-(1-hydroxy)-piperidine-1-yl imidazole;
2-(4-Fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)-4-(3a-hydroxy-N-tert.butyloxycarbonylnortropan-3b-yl) imidazole;
2-(4-Fluorophenyl)-4-(1-methyl-4-hydroxypiperidin-4-yl)-1-(2-cyclohexylamino-4-pyrimidinyl)imidazole;
2-(3-Trifluoromethylphenyl)-4-(1-methyl-4-hydroxypiperidin-4-yl)-1-(2-cyclopropylamino-4-pyrimidyl)imidazole;
2-(3-Trifluoromethylphenyl)-4-(1-methyl-4-hydroxypiperidin-4-yl)-1-(2-cyclopentylamino-4-pyrimidyl)imidazole;
2-(4-Fluorophenyl)-1-(2-cyclopentyl)amino-4-pyrimidyl)-4-(4-(2-hydroxy-2-methyl)propylpiperidine-1-yl imidazole;
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidyl)-4-(3a-hydroxy-nortropan-3b-yl) imidazole; and
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4pyrimidyl)-4-(4-acetyl)piperidine-1-yl imidazole.
It will be appreciated that when Y is substituted alkylene the compounds of formulae II and III contain at least 1 assymetric carbon atom with this alkylene moiety. The resulting diastereoisomers and enantiomers are encompassed by the instant invention. Preferably, however, e.g. for pharmaceutical use in accordance with the invention, the compounds of formulae II and III, are provided in pure or substantially pure epimeric form, e.g. as compositions in which the compounds are present in a form comprising at least 90%, e.g. preferably at least 95% of a single epimer (i.e. comprising less than 10%, e.g. preferably less than 5% of other epimeric forms). Preferred epimeric compounds of formulae II and III are described hereinafter in the Examples.
In the present description the terms such as xe2x80x9cC3-C18heteroaryl, C4-C19heteroaralkyl and C3-C18heterocycloalkylxe2x80x9d denote heteroaryl, heteroaralkyl or heterocycloalkyl substituents comprising at least 3 ring atoms, at least one of which is a hetero atom, e.g. N, O or S, and which in the case of C4-C19heteroaralkyl groups are attached via an alkylene moiety comprising at least 1 carbon atom. Also in the present description the term xe2x80x9cheteroarylxe2x80x9d includes unsaturated cyclic moieties containing heteroatoms, including furyl, benzofuryl, thienyl and the like.
The novel oxazoles and imidazoles of the invention, in particular the compounds of formulae II, IIxe2x80x2, III and IIIxe2x80x2 and the specific compounds listed above are hereinafter referred to xe2x80x9cAgents of the Inventionxe2x80x9d.
The Agents of the Invention which comprise free hydroxyl groups may also exist in the form of ester, e.g. pharmaceutically acceptable, physiologically cleavable esters, and as such are included within the scope of the invention. Such pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or cleavage under physiological conditions to the corresponding Agents of the Invention which comprise free hydroxyl groups. Suitable pharmaceutically acceptable prodrug esters are those derived from a carboxylic acid, a carbonic acid monoester or a carbamic acid, advantageously esters derived from an optionally substituted lower alkanoic acid or an arylcarboxylic acid.
Agents of the Invention may also exist in the form of salts, e.g. pharmaceutically acceptable salts, and as such are included within the scope of the invention. Pharmaceutically acceptable salts include acid addition salts with conventional acids, for example, mineral acids, e.g., hydrochloric acid, sulfuric or phosphoric acid, or organic acids, for example, aliphatic or aromatic carboxylic or sulfonic acids, e.g., acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric hydroxymaleic, pyruvic, pamoic, methanesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; also amino acids, such as arginine and lysine. For compounds of the invention having acidic groups, for example, a free carboxy group, pharmaceutically acceptable salts also represent metal or ammonium salts, such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed with ammonia or suitable organic amines.
Agents of the Invention of formula IIxe2x80x2
wherein Rxe2x80x213, Rxe2x80x215, R10 and Z are as previously defined and Wxe2x80x3 is xe2x80x94NHxe2x80x94, may be prepared by reacting the corresponding precursor compound of formula IV or IVxe2x80x2
wherein Rxe2x80x213 and R10 are as previously defined, with the corresponding Rxe2x80x215xe2x80x94NH2 derivative. For example, the reaction may be carried out by refluxing the reactants in an organic solvent, e.g. dichloroethane, e.g. in the presence of diethoxytrifluoroborane. Thereafter, if desired, the compound of Formula IIxe2x80x3 obtained nay be converted into a further compound of Formula IIxe2x80x3 or otherwise treated as required.
The precursor compound of formula IV may be prepared by controlled oxidation of the corresponding 5(2-methylthio-4-pyrimidyl)-4-phenylimidazole, e.g. employing an oxidising agent such as mCPBA (meta chloroperbenzoic acid), conveniently in an organic solvent such as methylene chloride. The corresponding 5(-4-pyrimidyl/pyridyl)-4-phenyloxazole compound may be prepared by contacting the corresponding acetophenone precursor compound of formula V or Vxe2x80x2
wherein R10 is as defined above, with a corresponding amide of formula Rxe2x80x213C(O)NH2, typically at elevated temperature. The compounds of formula V and Vxe2x80x2 may be prepared by bromination of the corresponding acetophenone, e.g. 2-(2-methylthio-4-pyrimidyl)acetophenone. The acetophenone precursor may be prepared by reacting the corresponding N-methoxy-N-methylbenzamide with the corresponding pyrimidine, e.g. 4-methyl-2-(methylthio)pyrimidine, for instance in a THF containing organic solvent with cooling.
Thus in a further aspect the invention includes a process for the preparation of a compound of formula IIxe2x80x3
wherein Rxe2x80x213, Rxe2x80x215, R10 and Z are as previously defined and Wxe2x80x3 is xe2x80x94NHxe2x80x94, which comprises reacting the corresponding precursor compound of formula IV or IVxe2x80x2
wherein Rxe2x80x213, R10 and Z are as previously defined, with the corresponding Rxe2x80x215xe2x80x94NH2 amine, and thereafter, if desired, converting the compound of formula IIxe2x80x3 obtained into a further compound of formula IIxe2x80x3 or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof.
Agents of the Invention of formula IIIxe2x80x3
wherein Rxe2x80x223, Rxe2x80x225 and R10 are as previously defined and Wxe2x80x2xe2x80x3 is xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94, may be prepared by reacting the corresponding compound of formula Ixe2x80x3 in which Rxe2x80x223 is halogen, e.g. Br, with the corresponding Rxe2x80x223 ketone or activated Rxe2x80x223 precursor, e.g. tri-alkylstannyl activated Rxe2x80x223 precursor. For example, the reaction may be carried out, e.g. in the presence of reducing agent, such as BuLi or PdCl2(PPh3)2, by refluxing the reactants, and/or with cooling, in an organic solvent, as appropriate. Thereafter, if desired, the compound of Formula IIIxe2x80x3 obtained may be converted into a further compound of Formula IIIxe2x80x3 or otherwise treated as required.
The compound of formula IIIxe2x80x3 in which Rxe2x80x223 is halogen, e.g. Br, may be prepared reacting the corresponding precursor compound of formula VI 
wherein R10 is as previously defined with the corresponding Rxe2x80x225xe2x80x94NH2 or Rxe2x80x225xe2x80x94OH derivative. For example, the reaction may be carried by refluxing the reactants in an organic solvent, e.g. dichloroethane, e.g. in the presence of diethoxytrifluoroborane.
The corresponding 1(2-methylthio-4-pyrimidyl)-2-phenyl-4-bromo-imidazole compound may be prepared by reacting the corresponding 2-phenyl-4-bromo-imidazole compound with 4-chloro-2-methylthiopyrimidine, e.g. in the presence of KN(TMS)2 in an organic solvent such as DMF. The 2-phenyl-4-bromo-imidazole compound may be obtained by removal of the trimethylsilanyl-ethoxymethyl from the corresponding 1-trimethylsilanyl-ethoxymethyl-2-phenyl-4-bromo-imidazole compound, which in turn may be prepared from 4,5-dibromo compound, which in turn may be prepared by phenylation of the known compound, 2,4,5-tribromo-1-(2-trimethylsilanyl-ethoxymethyl)imidazole (Tetrahedron Letters (1998), 39(29),5171-5174); for instance as hereinafter described in the Examples.
Thus in a further aspect of the invention includes a process for the preparation of a compound of formula IIIxe2x80x3
wherein Rxe2x80x223, Rxe2x80x225 and R10 are as previously defined and Wxe2x80x2xe2x80x3 is xe2x80x94NHxe2x80x94 or xe2x80x94Oxe2x80x94, comprising reacting a corresponding compound of formula IIIxe2x80x3 in which Rxe2x80x223 is halogen, e.g. Br, with the corresponding Rxe2x80x223 ketone or activated Rxe2x80x223 precursor, e.g. tri-alkylstannyl activated Rxe2x80x223 precursor, and thereafter, if desired, converting the compound of formula Ixe2x80x3 obtained into a further compound of formula IIIxe2x80x3 or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof.
Alternative processes for preparation of Agents of the Invention are described in the Examples and are included within the scope of the present invention.
The synthesis of Agents of the Invention is further described in the following Examples.